Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma

Yasuhiro Goto, Keiko Shinjo, Yutaka Kondo, Lanlan Shen, Minoru Toyota, Hiromu Suzuki, Wentao Gao, Byonggu An, Makiko Fujii, Hideki Murakami, Hirotaka Osada, Tetsuo Taniguchi, Noriyasu Usami, Masashi Kondo, Yoshinori Hasegawa, Kaoru Shimokata, Keitaro Matsuo, Toyoaki Hida, Nobukazu Fujimoto, Takumi KishimotoJean Pierre J. Issa, Yoshitaka Sekido

Research output: Contribution to journalArticle

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Abstract

Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets.

Original languageEnglish
Pages (from-to)9073-9082
Number of pages10
JournalCancer Research
Volume69
Issue number23
DOIs
Publication statusPublished - 01-12-2009

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Epigenomics
DNA Methylation
Genes
Methylation
Adenocarcinoma
CpG Islands
Histone Deacetylase Inhibitors
Comparative Genomic Hybridization
Adenocarcinoma of lung
Malignant Mesothelioma
Chromatin Immunoprecipitation
Pathologic Processes
Tumor Suppressor Genes
Histones
Lysine
Cluster Analysis
Disease Progression
Neoplasms
Thorax
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Goto, Y., Shinjo, K., Kondo, Y., Shen, L., Toyota, M., Suzuki, H., ... Sekido, Y. (2009). Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. Cancer Research, 69(23), 9073-9082. https://doi.org/10.1158/0008-5472.CAN-09-1595
Goto, Yasuhiro ; Shinjo, Keiko ; Kondo, Yutaka ; Shen, Lanlan ; Toyota, Minoru ; Suzuki, Hiromu ; Gao, Wentao ; An, Byonggu ; Fujii, Makiko ; Murakami, Hideki ; Osada, Hirotaka ; Taniguchi, Tetsuo ; Usami, Noriyasu ; Kondo, Masashi ; Hasegawa, Yoshinori ; Shimokata, Kaoru ; Matsuo, Keitaro ; Hida, Toyoaki ; Fujimoto, Nobukazu ; Kishimoto, Takumi ; Issa, Jean Pierre J. ; Sekido, Yoshitaka. / Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. In: Cancer Research. 2009 ; Vol. 69, No. 23. pp. 9073-9082.
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abstract = "Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3{\%}) and 544 genes (8.8{\%}) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11{\%} of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20{\%}) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets.",
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Goto, Y, Shinjo, K, Kondo, Y, Shen, L, Toyota, M, Suzuki, H, Gao, W, An, B, Fujii, M, Murakami, H, Osada, H, Taniguchi, T, Usami, N, Kondo, M, Hasegawa, Y, Shimokata, K, Matsuo, K, Hida, T, Fujimoto, N, Kishimoto, T, Issa, JPJ & Sekido, Y 2009, 'Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma', Cancer Research, vol. 69, no. 23, pp. 9073-9082. https://doi.org/10.1158/0008-5472.CAN-09-1595

Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. / Goto, Yasuhiro; Shinjo, Keiko; Kondo, Yutaka; Shen, Lanlan; Toyota, Minoru; Suzuki, Hiromu; Gao, Wentao; An, Byonggu; Fujii, Makiko; Murakami, Hideki; Osada, Hirotaka; Taniguchi, Tetsuo; Usami, Noriyasu; Kondo, Masashi; Hasegawa, Yoshinori; Shimokata, Kaoru; Matsuo, Keitaro; Hida, Toyoaki; Fujimoto, Nobukazu; Kishimoto, Takumi; Issa, Jean Pierre J.; Sekido, Yoshitaka.

In: Cancer Research, Vol. 69, No. 23, 01.12.2009, p. 9073-9082.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma

AU - Goto, Yasuhiro

AU - Shinjo, Keiko

AU - Kondo, Yutaka

AU - Shen, Lanlan

AU - Toyota, Minoru

AU - Suzuki, Hiromu

AU - Gao, Wentao

AU - An, Byonggu

AU - Fujii, Makiko

AU - Murakami, Hideki

AU - Osada, Hirotaka

AU - Taniguchi, Tetsuo

AU - Usami, Noriyasu

AU - Kondo, Masashi

AU - Hasegawa, Yoshinori

AU - Shimokata, Kaoru

AU - Matsuo, Keitaro

AU - Hida, Toyoaki

AU - Fujimoto, Nobukazu

AU - Kishimoto, Takumi

AU - Issa, Jean Pierre J.

AU - Sekido, Yoshitaka

PY - 2009/12/1

Y1 - 2009/12/1

N2 - Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets.

AB - Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets.

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